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Invited researcher Shoenfeld Yehuda
Contract number
14.W03.31.0009
Time span of the project
2017-2021

As of 15.02.2021

21
Number of staff members
31
scientific publications
6
Objects of intellectual property
General information

Name of the project: Creation of the Laboratory of the Mosaic of Autoimmunity for studying causes and mechanisms of autoimmune diseases and usage of immunological tools for their diagnostics and treatment

Strategy for Scientific and Technological Development Priority Level: в

Goals and objectives

Research directions:

  • Experimental therapy of insular sclerosis on a model of allergic encephalomyelitis
  • Autoimmune links of pathogenesis of саркоидоза
  • Etiology and pathogenesis of autoimmune thyroid diseases in particular of autoimmune Hashimoto's thyroiditis

Project objective: Creation of a laboratory for research of autoimmunity at the Saint Petersburg State University to organize translation medicine research of autoimmunopathy using methods and approaches that have been earlier successfully used by the leading scientist in rheumatological and autoimmune disease.

The practical value of the study
  1. On the model of multiple sclerosis in mice, the scheme of its experimental therapy has been shown. The introduction of tuftsin-phosphorylcholine inhibits the development of the disease and facilitates its course. There is a dependence of the effectiveness of experimental therapy on the dose and regimen of drug administration; the drug reduces the degree of lymphoid infiltration and demyelination in the lesions. For the first time, the effectiveness of this method in relation to autoimmune diseases of the central nervous system has been shown.
  2. The study of the immune complexes in patients with sarcoidosis showed that they contribute in the in vitro formation of the complexes of blood plasma with antigens of homologous tissues affected by granulomatous inflammation and does not form such complexes with marker antigens of tuberculous mycobacteria. The study of the spectrum of autoimmunity showed that 33% of patients with sarcoidosis are characterized by an increase in the titer of autoantibodies to citrulinated vimentin. The relationship between the occurrence of sarcoidosis and some anamnestic risk factors for its development, including adjuvant-like ones, turned out to be reliable, which brings sarcoidosis closer to the adjuvant-induced autoimmune-autoinflammatory syndrome (ASIA). In sarcoidosis, the existence of manifestations of small nerve fiber polyneuropathy, characteristic of autoimmunopathies, has been demonstrated. The features of the spectrum of autoimmunity and subpopulations of blood lymphocytes in sarcoidosis and tuberculosis similar to it were found. A formula has been developed that makes it possible to clarify the differential diagnosis of these diseases. Hyperprocalcitoninemia was revealed for the first time in sarcoidosis, which can be interpreted as confirmation of the role of infection in its etiology.
  3. When studying the relationship between Hashimoto's autoimmune thyroiditis (AIT) and psychosis, the influence of prolactin, free thyroxine, autoantibodies to thyroglobulin on the development of mental disorders was established. Cases of autoimmune limbic encephalitis with anti-neuroreceptor autoantibodies mimicking Hashimoto's encephalopathy have been identified. For the first time, an experimental model of Hashimoto's encephalopathy was obtained in mice with intracisternal injection of IgG patients, and some of its behavioral symptoms were reproduced. In mentally ill patients with AIT, hyperprolactinemia not associated with the drug treatment was revealed. There was no significant connection between mental disorders and titers of autoantibodies to thyroperoxidase, while in mentally ill persons with AIT three times more often, compared with mentally healthy persons with AIT, the concentrations of autoantibodies to alpha-enolase were increased. The level of the latter in mentally ill individuals with AIT correlated with the signs of hypothyrosis and some neuropsychiatric symptoms, as well as with the concentrations of the pro-inflammatory cytokine - IL-1b and the key cytokine of Th17-dependent immune responses - IL-21. A number of symptoms of mental disorders in AIT were found to correlate with the concentrations of pro-inflammatory cytokines. The regularly developing hyperprolactinemia was described, as well as a high frequency of prolactinomas and inhomogeneous echostructure of the pituitary gland during magnetic resonance imaging in persons suffering from AIT and obese patients with pink striae (Simpson-Page syndrome). A new concept about the organic nature of the latter, previously considered a functional disorder and its role as a risk factor by prolactin, has been proposed. The prominent data on the subpopulation composition of peripheral blood T-lymphocytes in AIT patients was obtained (decrease in the proportion of Th1 lymphocytes and twice negative (CCR4 – CXCR3–) Th17, increase in the proportion of twice positive (CCR4 + CXCR3 +) Th17, changes in Tfh subpopulations). For the first time in the world literature, the metabolism of ferritin in AIT has been described, an increase in its concentrations in a new coronavirus infection comorbid with AIT and a decrease in the levels of autoantibodies markers for AIT have been revealed.
  4. In reproductive studies, an experimental model of autoimmune infertility was obtained by injecting experimental female mice with IgG from women who have lost their reproductive potential due to AIT. IgG of patients (but not from the healthy donors) caused pregnancy termination, fetal resorption, a decrease in the volume and weight of the placenta, a desctruction of its structure, and a decrease in the number of conceptions. The pathomorphological and pathophysiological mechanisms of these disorders were revealed (decreased expression of annexin V and changes in the structural and functional characteristics of trophoblastic cells). In a clinical and pathophysiological study, a similar relationship between AIT in women and the termination and unfavorable outcome of pregnancy and IVF procedures was confirmed. Thus, the pathogenetic role of IgG in patients with AIT in pregnancy abnormalities, placentogenesis and fetogenesis has been proved.
  5. In the study of the autoimmune dysautonomia, priority new data were obtained, indicating that various forms of chronic fatigue falling under the criteria of myalgic encephalomyelitis - chronic fatigue syndrome (ME/CFS). The most typical for all etiological variants of ME/CFS was an increase in the level of autoantibodies to beta2-glycoprotein 1. Autoimmunity to antigens of the nervous tissue and non-organ-specific autoantigens increased more significantly than to organ-specific autoantigens, which indicates a secondary, disautonomic complaints of somatic dysfunction in such patients. There were positive and negative correlations described in the level of autoantibodies with the symptoms of the ME/CFS. For the first time it was shown that, in comparison with the control group of women operated on the mammary gland without the use of silicone, after its silicone arthroplasty, a significant increase in the concentration of autoantibodies to TSH receptors to a pathological level occurs within a year. Before a planned, more or less long-awaited operation on the mammary gland, regardless of its type, there is a preoperative transient hyperprolactinemia, probably of psychogenic origin, which is compensated within 3-6 months after the operation. During the first year after breast surgery, the number of women with positive ASIA criteria increased. ASIA symptoms correlated with an increase in the concentration of some non-organ-specific autoantibodies, which, however, did not go beyond the normal range during this period. In women with long-term (3-15 years) wearable silicone breast implants, a number of ASIA manifestations similar to the clinical picture of ME/CFS were noted. At the same time, women with long-term wearable silicone breast implants (compared with healthy women without implants) showed a highly significant decrease in serum concentrations of autoantibodies to several G-protein-coupled receptors of autonomic bioregulators, and the levels of such autoantibodies negatively correlated with manifestations of dysautonomia and depressive symptoms. It was found that dysautonomia during silicone implantation is not a purely neural, but a neuroimmune disorder. A certain level of the autoantibodies to the receptors of the autonomic nervous system is inherent in healthy individuals and is it necessary to provide the adequate autonomic regulation. Not autoimmunity per se, but only an inadequate (increased or decreased) titer of autoantibodies leads to the dysfunction and disease progression. Therefore, a new interpretation of ASIA syndrome as a prenosological condition caused by prolonged overstrain of immunoneuroendocrine regulation has been proposed.
  6. In the studies with oncological patients it has been shown that inhibitors of T-lymphocyte checkpoints cause ASIA symptoms regardless of the presence or absence of previous autoimmune diseases and from various types of anamnestic trigger effects. This characterizes the degree of immune stimulation caused by these drugs, leading to autoimmune manifestations even in individuals without a history of predisposing factors. In a large cohort of patients with AIT, a tendency to lymphocytosis and a high incidence of comorbid lymphoproliferative neoplastic diseases in AIT were revealed.
  7. Geoepidemiological studies revealed an extreme unevenness of the regional distribution of the incidence of autoimmunopathies (type 1 diabetes mellitus, rheumatoid arthritis, Graves-von Basedow's disease) in the Russian Federation and a tendency to an increase in their incidence over the studied period. A statistically significant relationship was found between the unevenness of the regional distribution of autoimmune diabetes mellitus (both in adults and children) in Russia with anthropogenic factors of the automobile and road complex, and in children - with the intensity of pollution of surface water sources in the region. The relationship between the regional incidence of autoimmunopathies and the concentration of some microelements (mercury, iodine, aluminum) in the hair was revealed. Using the Jaccard coefficient, the similarity of the distribution of the incidence of major autoimmune diseases in the regions of the Russian Federation was studied.

Implemented results of research:

  • The method of staining histological matherial for the “Comparative Analysis of Infiltration Methods of Human Skin Tissue” has been improved and implemented at the Resource Center "Development of Molecular and Cellular Technologies" of the St. Petersburg State University Science Park. It is applicable and important for diagnostic tasks, given the significant (more than 10 hours) time savings.
  • "A GUIDE TO AUTOIMMUNE DISEASES FOR GENERAL PRACTICIONERS", ed. Y. Shoenfeld, P.L. Meroni, L.P. Churilov is applied in the educational process at the St. Petersburg State University. The manual is officially approved as a mandatory book for the academic discipline "Autoimmunology" (part 1), "Autoimmunology" (part 2) as part of the curriculum.
  • The monograph by Yu.A. Fesenko, L.P. Churilov, V.A. Khudik et al. "NEUROSES AND STRESS" has been introduced into the educational process and work programs at the Federal State Budgetary Educational Institution of Higher Education of the St. Petersburg State Medical University of the Ministry of Health of Russia.
  • "Reproductively significant autoimmune diseases in the ART clinic" and "Autoimmune diseases and programming of pregnancy" are introduced into the educational process (Basic educational residency program "Obstetrics and Gynecology" in the specialty 31.08.01 "Obstetrics and Gynecology") in St. Petersburg State University and Scientific Research Institute of the Obstetrics, Gynecology and Reproductive techniques.
  • According to the obtained patent "A method for predicting the development of tuberculosis in healthy persons", the method was introduced into the practice of the Scientific Research Institute of Phthisiopulmonology.
  • The results of studying the immunoendocrine parameters of reactivity after silicone breast prosthetics made it possible to clarify the indications and contraindications, supplement the preoperative examination scheme and were introduced into the practice of plastic surgery clinics in St. Petersburg and Krasnodar.
  • Diagnostics of small fiber neuropathies using confocal microscopy has been developed.

Education and career development:

  • The working programs of two new elective training courses in autoimmunology have been developed and approved at St. Petersburg State University. They have been introduced into the curriculum from the 2018-19 academic year. In 2017-2019, the leading scientist lectured students and postgraduates of St. Petersburg State University and conducted training seminars with them with a total of up to 50 academic hours annually.
  • Workbook on the experimental and clinical pathology for students of the specialties "General Medicine" and "Dentistry" (3rd edition, ed. Churilov L.P., St. Petersburg, Spetslit, 2017, 599 p.) is revised and enlarged. It is used in the educational process and is available to all students.
  • Laboratory staff successfully trained in a specialized center and improved their qualifications, participated in international and Russian forums.
  • Laboratory staff and students from St. Petersburg State University were trained by the world's leading autoimmunologists and pathologists under the Autoimmunity Academy program (Lisbon, May 14-16, 2018). For 4.5 years of functioning of the Laboratory, its employees received 132 Certificates of advanced training.
  • In 2020, new educational courses were created and introduced into the educational process: “Reproductively significant autoimmune diseases in the ART clinic”, “Autoimmune diseases and planning of pregnancy” (Niauri D.).
  • Since 2017 two Ph.D. dissertations were prepared and defended, two diplomas of specialists, one diploma of an intern.
  • Two textbooks and two teaching aids have been published and introduced into the educational process.
  • At scientific events, 48 invited reports, 37 oral reports and 33 poster presentations were made.

Infrastructure transformations:

Since 2017, the research plans of the laboratory and the leading scientist have had the full support of St. Petersburg State University. At the same time, new branches of the existing three main scientific areas arise, for example, "Immunoplastic aspects of plastic surgery", "Study of the role of adjuvants in autoimmune diseases and the study of the geographical features of autoimmune diseases in the Russian Federation." In addition to the rooms of the Laboratory provided by St. Petersburg State University (with a total area of 111.7 sq. m.), equipped for the primary processing of blood samples, storage of biomaterials, with the workplaces of the leading scientist and employees of the laboratory and conference hall, the employees of the Laboratory actively use the rooms of the Science Park of St. Petersburg State University: 1) Resource center for the development of molecular and cellular technologies; 2) GLP-standard vivarium of the Institute of Translational Biomedicine, St. Petersburg State University. 3) Clinic of high medical technologies of St. Petersburg State University. The SPbU Science Park has all the equipment required to carry out scientific research on the project. The laboratory has mastered the equipment of the SPbSU Science Park, which is necessary to fulfill all the planned tasks of the project, and in addition, it has acquired and is using additional equipment necessary for optimal logistics of biomaterial processing (a Liebher refrigerated cabinet (Austria) for storing reagents, a Liebher freezer (Austria) for storing samples plasma and serum, laboratory medical centrifuge ELMI CM-6M (Latvia), electronic analytical scales (CJSC MASSA-K, Russia) for primary processing of blood samples). Clinical and pathophysiological examinations of patients and part of laboratory tests are carried out by laboratory staff at clinical and scientific and educational bases, - Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, Psychiatric Hospital named after. P.F. Kashchenko, Institute of Experimental Medicine. On the basis of an agreement on the provision of services, part of the standard clinical and laboratory examinations of patients was carried out at the Laboratory for the Diagnosis of Autoimmune Diseases of the SPbSMU named after I.P. Pavlov, Research Institute of Experimental Medicine and Research Institute of Phthisiopulmonology, the Regional Oncological Dispensary and the clinic “Baltmed”. With the agreement on scientific cooperation, the collections of biomaterials of the St. Petersburg city pathoanatomical bureau are used.

In the future, the laboratory needs to expand its own clinical and diagnostic capabilities of the Clinic of High Medical Technologies of St. Petersburg State University in relation to therapeutic and prophylactic treatment of the autoimmune diseases.

Other results:

  • Staff of the Laboratory have organized and run an international congress in autoimmune diseases «Bridge between East and West» which is the largest of such events in this domain of Russian science. 50 leading international autoimmunologists and over 600 Russian and international students, postgraduates, MDs and scientists took part in the congress. After the congress Russian participants including employees of the Laboratory received certificates of additional training in continuing medical education.
  • The Laboratory has won the grant of the Russian Foundation for Basic Research for conducting the «4th Academy of Autoimmunity» in 2019.

Collaborations:

  1. Zabludovich Center for Autoimmune Diseases. Joint research on the subject of the grant (experimental therapy of multiple sclerosis on a model), joint scientific events (seminars of scientists from this center - Y. Shoenfeld, B. Gilburd, M. Blank, H. Amital, - in the Laboratory of Autoimmunity Mosaic, internships for laboratory staff - at the Zabludovich Center). Joint publications.
  2. Laboratory for the diagnosis of autoimmune diseases, St. Petersburg State Medical University named after acad. I.P. Pavlov. Joint research (in the areas of "Immunopathological lung diseases" and "Autoimmune lesions of the thyroid gland"), joint scientific activities (employees of the Pavlov First St. Petersburg State Medical University participated in Y. Shoenfeld's seminars in the Laboratory).
  3. Department of General Pathology and Pathological Physiology of the Institute of Experimental Medicine. Joint research, joint scientific events (Laboratory staff participated in the 6th International Symposium "Interaction of the nervous and immune systems in health and disease, organized by the Institute of Experimental Medicine (E.A. Korneva, I. Shenfeld, L.P. Churilov, Yu. I. Stroyev), employees of the Institute - in scientific seminars conducted by Y. Shoenfeld in the Laboratory).
  4. St. Petersburg Research Institute of Phthisiopulmonology. Joint research (employees combine clinical work at the Institute and scientific work at St. Petersburg State University, direction "Immunopathological lung diseases") joint scientific activities (Laboratory staff - L.P. Churilov, Y. Shoenfeld - join the meetings of the Scientific Council at the Research Institute of Phthisiopulmonology with scientific reports).
  5. 5. Institute of Translational Biomedicine, St. Petersburg State University. Joint research (modeling of autoimmunopathies in animals), joint scientific events, publications and reports at conferences.
  6. Research Institute of Obstetrics, Gynecology and Reproductology held technical and methodological consultations in mastering the technique of morphometric analysis of biomaterial obtained in an experimental model of autoimmune mechanisms of the pathogenesis of infertility.
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Под ред. И. Шенфельда, П.Л. Мерони, Л.П. Чурилова, пер. с англ. Л.П. Чурилова
РУКОВОДСТВО ПО АУТОИММУННЫМ ЗАБОЛЕВАНИЯМ ДЛЯ ВРАЧЕЙ ОБЩЕЙ ПРАКТИКИ/ СПб.: Медкнига-ЭЛБИ, 2017. – 416 с.: 89 табл., 75 рис. (GUIDELINES ON AUTOIMMUNE DISEASES FOR GENERAL PRACTITIONERS / Ed. Y Shoenfeld, P.L. Meroni, L.P. Churilov, translation. from English L.P. Churilov. - SPb.: Medkniga-ELBI, 201 .-- 416 p .: 89 tab., 75 fig.)
Ryabkova, V.A., Shubik, Y.V., Erman, M.V., Churilov, L.P., Kanduc, D., & Shoenfeld, Y.
Lethal immunoglobulins: Autoantibodies and sudden cardiac death //Autoimmun Rev. 2019 Apr;18(4):415-425. doi: 10.1016/j.autrev.2018.12.005.
Kudryavtsev I, Serebriakova M, Starshinova A, Zinchenko Y, Basantsova N, Malkova A, Soprun L, Churilov LP, Toubi E, Yablonskiy P, Shoenfeld Y.
Imbalance in B cell and T Follicular Helper Cell Subsets in Pulmonary Sarcoidosis. Sci Rep. 2020 Jan 23;10(1):1059. doi: 10.1038/s41598-020-57741-0.
Borba V, Malkova A, Basantsova N, Halpert G, Andreoli L, Tincani A, Amital H, Shoenfeld Y.
Classical Examples of the Concept of the ASIA Syndrome. Biomolecules. 2020 Oct 12;10(10):1436. doi: 10.3390/biom10101436.
Shoenfeld, Y., Ryabkova, V., Scheibenbogen, C., Brinth, L., Martinez-Lavin, M., Ikeda, S., Heidecke, H., Watad, A., Bragazzi, N., Chapman, J., Churilov, L., Amital, H.
Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.Clin Immunol. 2020 May;214:108384. doi: 10.1016/j.clim.2020.108384.
Золотых В.Г., Гвоздецкий А.Н., Ким А.Я., Лапин С.В., Михайлова Л.Р., Старовойтова Е.М., Федоткина Т.В., Чурилов Л.П., Шенфельд И., Яблонский П.К.
ВЛИЯНИЕ СИЛИКОНОВОЙ МАММОПЛАСТИКИ НА ИММУНОЭНДОКРИННЫЙ СТАТУС ЖЕНЩИН-РЕЦИПИЕНТОК. Medical Immunology (Russia) [Медицинская иммунология] 2020. Т. 22. № 5. С. 957-968.
Churilov LP, Sobolevskaia PA, Stroev YI.
Thyroid gland and brain: Enigma of Hashimoto's encephalopathy. Best Pract Res Clin Endocrinol Metab. 2019 Dec;33(6):101364. doi: 10.1016/j.beem.2019.101364.
Pashnina, I., Krivolapova, I., Fedotkina, T., Ryabkova, V., Chereshneva, M., Churilov, L., Chereshnev, V.
Antinuclear Autoantibodies in Health: Autoimmunity Is Not a Synonym of Autoimmune Disease. Antibodies (Basel). 2021 Feb 25;10(1):9. doi: 10.3390/antib10010009.
Borodina E, Katz I, Antonelli A, Gzgzyan AM, Dzhemlikhanova LK, Ostrinski Y, Niauri D, Khizroeva J, Bitsadze V, Makatsariya A, Tincani A, Nalli C, Churilov LP, Shovman O, Halpert G, Blank M, Shoenfeld Y, Amital H.
The pathogenic role of circulating Hashimoto's Thyroiditis-derived TPO-positive IgG on fetal loss in naive mice. Am J Reprod Immunol. 2021 Jan;85(1):e13331. doi: 10.1111/aji.13331.
Novikova NS, Diatlova AS, Derevtsova KZ, Korneva EA, Fedotkina TV, Ostrinski Y, Abraham L, Quinn S, Segal Y, Churilov LP, Blank M, Shoenfeld Y, Aharoni R, Amital H
Tuftsin-phosphorylcholine attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol. 2019 Dec 15;337:577070. doi: 10.1016/j.jneuroim.2019.577070.
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